Aminotrexate(tm) (AMT) is an antifolate in the same class as MIX that we have established is nearly 100% orally bioavailable in humans with a lower interpatient coefficient of variation than MTX, and is much more rapidly taken up by cells and tissues. With regard to non-CNS toxicities and response to the antidote leucovorin, AMT is indistinguishable from MTX. Accordingly, we hypothesize (clinical hypothesis 1) that oral AMT will be efficacious in a greater maximum fraction of patients with moderate-to-severe psoriasis than oral MTX, and/or reach a particular level of symptom improvement quicker than after oral MTX. We have also discovered that at equipotent doses of AMT and MTX, human CSF and animal brain parenchyma accumulate significantly less AMT than MTX. As such, we also hypothesize (clinical hypothesis 2) that oral AMT will result in fewer patients with postdosing neurotoxicity, and/or patients experiencing less severe postdosing neurotoxicity. As a result, AMT may potentially be better tolerated, resulting in better long-term adherence to AMT compared to MTX. If a greater fraction of patients with respond to AMT than to MTX, and/or can be treated longer without becoming intolerant to the side-effects, AMT could have a major impact on the standard of care in psoriasis and would have critical pharmacoeconomic consequences by obviating cost-intensive biologic treatments. This SBIR Fast-Track proposal aims to test the above hypotheses by conducting a series of two sequential Phase 2/3 clinical trials. In the first Phase 2 dose-finding clinical trial to be conducted in SBIR Phase I (36 subjects, 12 weeks per subject, 6-12 month enrollment period), the Specific Aims will be to: (1): assess the safety of oral AMT in the treatment of moderate-to-severe plaque psoriasis;(2) establish the dose- response relationship of oral AMT in moderate-to-severe plaque psoriasis;and (3) determine if splitting the weekly dose over two tablets, given every 12 hours, is preferred over giving the fully weekly dose once, using PASI scoring and safety assessments. From the Phase 2 study results we will select the dose of oral AMT that results in maximum efficacy and best time-to-response while not resulting in treatment-emergent toxicities or intolerance. We will then carry this oral AMT dose forward into the Phase 3 double-blind, randomized clinical trial to be conducted in SBIR Phase II (390 subjects, 26 weeks per subject, 30-36 month enrollment period) to test AMT vs. MTX head-to-head via the following Specific Aims: (1) Compare the efficacy of oral AMT and oral MTX in the treatment of subjects with moderate-to-severe plaque psoriasis who have not previously received MTX;and (2) Compare the safety and tolerance of AMT with MTX by comparing adverse events and laboratory parameters, expanded with a specific assessment of neurocognitive and CNS related-side effects of both drugs. The primary efficacy end-point is improvement in area under the PASI-N curve at Week 26, where PASI-N is the mean percent reduction in the Psoriasis Area-and-Seve'rity Index (PASI). Secondary efficacy and neurocognitive end-points include: proportion of subjects achieving PASI 50 and PASI 75 at Week 10 and Week 26;time to PASI 75 (Kaplan Meier);physician Global Assessment (PGA);Dermatology Life Quality (DLQI), Psoriasis Symptom Assessment (PSA);and neurocognitive scores from MMSE, FAClT-Fatigue, and FACT/GOG-Ntx. At the conclusion of the Phase 2 and 3 clinical trials proposed herein, we aim to have the necessary efficacy and safety data required for a Product License Application (NDA,) to the FDA for the use of AMT in psoriasis.